Seymour Kaufman (1924–2009)

Seymour Kaufman (1924–2009)

BY LOUIS SOKOLOFF

The American Society for Biochemistry and Molecular Biology recently lost another of its distinguished and longtime members. Seymour Kaufman, a scientist emeritus and former chief of the laboratory of neurochemistry at the National Institute of Mental Health, passed away at the age of 85 in Bethesda, Md.

Seymour was renowned for his contributions toward the characterizations of the partial reactions in processes catalyzed by mixed function oxidases, particularly those involved in the hydroxylation of aromatic amino acids. He identified tetrahydrobiopterin as an essential co-factor in these hydroxylation reactions. Seymour established, by direct enzyme assays, that it is indeed the lack of the phenylalanine hydroxylase enzyme that is responsible for the human genetic disease classical phenylketonuria. Subsequently, he identified other genetic variants of phenylketonuria that result from deficiencies in enzyme activities involved in the synthesis and processing of tetrahydrobiopterin, the co-factor in the phenylalanine hydroxylation reaction.

Seymour was born in Brooklyn, N.Y., on March 13, 1924. His earliest interests were not in science; at a young age, he showed artistic talents that led him to attend New York’s High School of Music and Art. The curriculum there was markedly deficient in science. Although Seymour never lost his interest in the arts, he, like so many others of his generation, was diverted to ambitions in science by reading Paul DeKruif’s “Microbe Hunters” during his senior year. This new interest initially was unfocused and fluctuated between basic chemistry and biochemistry. Eventually, having learned that the University of Illinois had an outstanding chemistry department and understanding that a strong background in chemistry would also be invaluable in biochemistry, he applied to the school and was admitted in 1941. During his undergraduate and graduate studies at the University of Illinois, he took most of the organic chemistry and biochemistry courses available and acquired extensive knowledge and experience in organic and synthetic chemistry, which proved to be valuable later in his career. His primary interest became biochemistry after he took W. C. Rose’s course in intermediary metabolism during his senior year in college. His interest was heightened while doing research for his master’s degree at the University of Illinois with Carl Vestling. It was this work with Vestling that led to Seymour’s first publication in the Journal of Biological Chemistry in 1946 (1).

After receiving his master’s degree in 1946, Seymour enrolled as a Ph.D. candidate under Hans Neurath in the department of biochemistry at Duke University. There, he worked with George Schwert and John Snoke on proteolytic enzymes, which stimulated an interest in enzymology that would remain with Seymour throughout his career. It was also in Neurath’s lab that he met Elaine Elkins, another of Neurath’s graduate students, who later became his wife.

After acquiring his Ph.D. in 1949 and doing a brief postdoctoral fellowship with Neurath, Seymour joined Severo Ochoa’s department of pharmacology at New York University, first as a postdoctoral fellow and then as an assistant professor. He remained there for approximately five years and matured into an outstanding enzymologist and scientist. The department had an extraordinarily stimulating atmosphere and was home to many great scientists. There was also the powerful influence of Ochoa’s character, personality and modus operandi. He was completely dedicated and focused on his research and uncompromisingly rigorous in its execution. Although Seymour probably would have denied it, he later displayed some of these traits while directing his own lab.

It was in Ochoa’s department that Seymour made his first important contribution to biochemistry. This was the characterization of the partial reactions in the conversion of alpha-ketoglutarate to succinate in the tricarboxylic acid cycle and the elucidation of the mechanism of the substrate-level phosphorylation associated with this step.

Giulio Cantoni had been in Ochoa’s lab during part of the time that Seymour was there and was very impressed with him. Cantoni later became chief of the laboratory of cellular pharmacology at the newly established NIMH and recruited Seymour as an independent research biochemist. In Ochoa’s lab, Seymour had been more or less required to work on projects of Ochoa’s choosing. Cantoni’s offer of complete freedom to choose his own research project was probably an important consideration in his decision to accept Cantoni’s offer and to join to the NIMH in 1954.

When Seymour arrived at the NIMH, he found that Cantoni’s laboratory was still under construction and would not be fully operational for several months. Although he was initially disappointed, he used this delay to deliberate on the choice of his first research project. He finally settled on the enzymatic hydroxylation of phenylalanine to tyrosine. The problem not only satisfied his interest in organic chemistry and his desire to contribute to biomedical research, but it was appropriate for the NIMH (even though he was not obligated to work on problems directly related to the brain), as the inability to convert phenylalanine to tyrosine results in phenylketonuria, which is characterized by mental deficiency.

Using partially purified enzymes from rat and sheep livers, Seymour developed a system that converted phenylalanine to tyrosine in vitro. In addition to oxygen, the reaction required NADPH and a boiled rat liver extract (i.e., “kochsaft”), indicating that there was an essential co-factor in the reaction. In a series of classical biochemical studies, he identified the co-factor as tetrahydropteridine and showed that it was formed from 7,8-dihydropteridine in the presence of NADPH. It was subsequently found that this compound is also an essential co-factor in other aromatic amino acid hydroxylations.

In 1968, the significance of Seymour’s contributions to neuroscience and to the research program of the NIMH was recognized by his appointment as chief of the laboratory of neurochemistry at the NIMH. From then on, his work largely, but not exclusively, concentrated on phenylketonuria. He finally proved that classical phenylketonuria was due to the lack of the phenylalanine hydroxylase enzyme. He also identified other variants of phenylketonuria, which were due not to lack of phenylalanine hydroxylase but to other enzymes involved in the synthesis of the essential co-factor tetrahydropteridine.

Seymour’s status in the world of biochemistry and his outstanding research contributions were honored by his selection to serve two terms on the editorial board of the American Journal of Biochemistry, election to the National Academy of Sciences and the American Academy of Arts and Sciences, the Meritorious Presidential Rank Award and the American Chemical Society Hillebrand Prize.

Although Seymour had decided that he lacked the talent to be a successful artist, he never lost his interest in art. He acquired an impressive collection of lithographs, woodcuts and paintings, some by Henri de Toulouse-Lautrec, whose work he particularly admired. His home also was filled with a number of sculptures produced by his daughter Emily, a very successful sculptor, who has one of her sculptures on display in the Hirshhorn Museum in Washington, D.C.

Seymour also had other interests to which, in his typical fashion, he was passionately devoted. Tennis was one of them. Although he lacked natural athletic talents and had never received any formal coaching, he developed a quite creditable tennis game, mainly because of his competitive nature. He hated to lose. He also developed a strong taste for good food. This probably evolved from several trips to France, during which he was introduced to the culinary magic of several of the three-star restaurants in the Michelin Guide.

Sadly, Seymour passed away on June 23, 2009. He had been ill for several years, but, during that time, he never lost his zest for life. He is survived by his wife, Elaine; son, Allan; daughters, Emily and Leslie; three grandchildren, Lisa, Joshua, and Amanda; and two sisters, Lilly Wolfe and Dottie Laiserin. He will be greatly missed by his family, friends, associates and by all in the biochemical community. Below, we offer thoughts and reflections from several of Seymour’s friends and colleagues.

The one word that best describes Seymour Kaufman’s approach to research is “careful.” He felt that to publish an erroneous datum or draw an unjustified conclusion would be a disaster, because it might deflect the progress of science. He once said that he spent 10 percent of his time being 90 percent sure and the remainder being 99.9 percent sure. Though this often delayed his publications, they never could have been any more respected by those who knew him well. His ability to draw valid conclusions and useful hypotheses from data was unsurpassed. His curiosity made the process of investigation a treasure hunt.

Seymour imbued his fellows with the same high technical and behavioral standards. He was not free with praise but was similarly stingy with opprobrium. One of my proudest moments as a postdoctoral fellow came after he suggested I repeat some experiments in a slightly different way. I must have visibly sagged, because he clapped me on the shoulder and said, “Look, I know you’re working like a dog.” It was a compliment to cherish. Seymour made his fellows realize he was genuinely interested in their work, fair in his evaluations and generous with his time. He claimed to enjoy being interrupted by fellows’ comments and questions because they provided some variety for the intensity of his focus. He was a superb teacher, an outstanding and creative investigator and a highly moral human being.

Ephraim Levin
Retired captain
U.S. Public Health Service

***

My memories of Seymour Kaufman date to 1965, when I came to the Bethesda campus of the NIMH as a visiting scientist from Sydney, Australia. Much of my research prior to this appointment was concerned with the metabolism of organic acids and their CoA derivatives in plants. I was, therefore, quite familiar with Seymour’s pioneering research with animals in this field, and he became one of my early acquaintances. At this time, Seymour and I were both in Giulio Cantoni’s laboratory of general and comparative biochemistry; I had joined the section on alkaloid biosynthesis, and Seymour was chief of the section on cellular regulatory mechanisms. Giulio’s laboratory sponsored a marvelous journal club for discussing interesting research papers; members included Harvey Mudd, David Neville, Howard Nash, Lou Sokoloff and Jack Durell. Seymour’s presentations provided important lessons in the importance of a rational, rigorous and critical approach to research. Some less academic memories include the times when Seymour and I spent many enjoyable weekends playing doubles tennis with Lou Sokoloff and Jack Durell. In 1987, the section on alkaloid biosynthesis was discontinued, and I was fortunate to be invited by Seymour to join his laboratory of neurochemistry. My collaboration with Seymour on the mechanism of nitric oxide synthesis represented a wonderful finale during the decade before my retirement. I cherish fond memories of a good friend, colleague and mentor.

John Giovanelli
Guest researcher
NIMH

***

Seymour and I were laboratory neighbors in the newly constructed clinical center at NIH in 1954. We quickly discovered that we both had switched from a high school art program to one in science, he in Brooklyn and I in Detroit. He already had established himself as an up-and-coming biochemist, and I was just getting started, and so, in addition to occasional discussions on diverse topics of mutual interest ranging from the arts to food and wine, he also served as a helpful informal adviser in matters of biochemical research. We both participated in a weekly journal club established by Giulio Cantoni, in which we presented either our own recent research results or reviewed an interesting journal article. I followed his pursuit of phenylketonuria and the nature of phenylalanine hydroxylation reaction like a serial detective story.